In response to NIA program announcement 99-049, Research Objective number 18: "Animal Models of Aging", we propose to apply a transgenic model of A2A adenosine receptor function to the study of neuroprotection, focusing primarily on the degeneration of nigrostriatal dopaminergic neurons that causes Parkinson's disease. Recently, adenosine receptors have emerged as potential targets for the modulation of cell death in the nervous system. Although a role for the A2A subtype of adenosine receptor has been suggested in ischemic and excitotoxic brain injury, the limited specificity, solubility and CNS accessibility of A2A receptor drugs have hindered progress. To overcome these pharmacological limitations and clarify the role of this receptor in neuronal cell death, we have developed a complementary transgenic model of A2A receptor inactivation. Our preliminary studies demonstrate attenuation of neurotoxicity in these A2A receptor knockout (KO) mice following transient focal ischemia or exposure to MPTP, a metabolic toxin that targets nigrostriatal neurons. We propose to build on these findings by further characterizing the features and beginning to identify the mechanisms of neuroprotection in A2A receptor-deficient mice. Specific Aim 1 seeks to investigate the survival and function of nigrostriatal neurons in MPTP-treated A2A KO mice. Specific Aim 2 is designed to provide pilot data on two broad mechanisms that may mediate the neuroprotective phenotype of A2A KO mice: presynaptic modulation of glutamate or dopamine release, and postsynaptic susceptibility to neurotoxic exposure. Thus, the exploration of this transgenic model of A2A receptor inactivation may provide new insight into the role of A2A receptors in neuronal cell death, and may encourage the development of novel therapeutic strategies for Parkinson's disease, stroke and other disorders of the aging nervous system.